The most well-known anthracycline anticancer drugs are doxorubicin and daunorubicin, which contain a 13-keto group. Doxorubicin, disclosed in U.S. Pat. No. 3,590,028, has a wide spectrum of anticancer utility and is used in the treatment of leukemias, lymphomas, and solid tumors. Daunorubicin, disclosed in U.S. Pat. No. 3,616,242, is useful in the treatment of acute leukemias. However, the utility of these drugs is limited by a serious side effect of cardiotoxicity so that the total amount of drug that can be given to a patient cannot exceed 550 mg/M2 (E. A. Lefrak et al., Cancer, 32:302, 1973). Even at or near the recommended maximum total cumulative dosage (430-650 mg/M2) significant and persistent heart dysfunction occurs in 60% of patients and 14% develop congestive heart failure. (A. Dresdale et al., Cancer, 52:51, 1983). Thus, while these drugs are useful to inhibit the growth of cancerous tumors, the patient may die of congestive heart failure because of the severe cardiotoxic side effect of the drugs.
It has also been found that the cardiotoxicity of these anthracyclines is produced by the metabolic reduction of the 13-keto moiety to a 13-dihydro alcohol metabolite (P. S. Mushlin et al., Fed. Proc., 45:809, 1986). In test systems where doxorubicin is not metabolized appreciably to the 13-dihydro alcohol metabolite (doxorubicinol) no significant cardiotoxic effects are observed (P. S. Mushlin et al., Fed. Proc., 44:1274, 1985; R. D. Olson et al., Fed. Proc., 45:809, 1986). In contrast, the 13-dihydro metabolites, doxorubicinol and daunorubicinol, produce cardiotoxicity in these same test systems at relatively low concentrations (1-2 micrograms/ml, R. D. Olson et al., Proceed. Am. Assoc. Cancer Res., 26:227, 1985; R. D. Olson et al., Proceed Am. Assoc. Cancer Res. 28:441, 1987).
If doxorubicin is allowed to remain in the test systems even for short periods of time some metabolic conversion occurs and the 13-dihydro metabolite is formed in sufficient quantity so that cardiotoxicity begins to develop (L. Rossini et al., Arch. Toxicol. Suppl., 9:474, 1986; M. Del Tocca et al., Pharmacol. Res. Commun., 17:1073, 1985). Substantial evidence has, thus, accumulated that the cardiotoxicity of drugs such as doxorubicin and daunorubicin results from the potent cardiotoxic effects produced by their 13-dihydro metabolites (P. Mushlin et al., FASEB Journal, 2:A1133, 1988; R. Boucek et al., J. Biol. Chem., 262:15851, 1987; and R. Olson et al., Proc. Natl. Acad. Sci., 85:3585, 1988; Forrest G L, et al., Cancer Res 60:5158, 2000).
It is known that doxorubicin in combination with the taxanes, such as paclitaxel, produces an enhanced anticancer effect in breast cancer, compared to either drug alone. Anticancer response rates with doxorubicin alone in breast cancer are 35-50%. With paclitaxel alone the response rate is 32-62%. However, in combination, these two drugs can produce response rates of 83-94% (Gianni L, et al., J Clin Oncol. 13:2688, 1995. Dombernowsk; P et al., Seminars in Oncology 23:23, 1996). Unfortunately, the combination of paclitaxel and doxorubicin can cause clinical congestive heart failure in 18-20% of patients (Gianni L, et al., J Clin Oncol. 13:2688, 1995; and Dombernowsk; P et al., Seminars in Oncology 23:23, 1996). Paclitaxel enhances the cardiotoxicity of doxorubicin which limits or precludes the use of anthracyclines in combination with taxanes. The incidence of congestive heart failure can be limited by reducing the dose of doxorubicin (Giordano S H et al., Clin Cancer Res 8:3360, 2002), but the efficacy of the combination can also be thereby reduced (Sparano J A et al., J Cin Oncol 17: 3828, 1999; Valero V, et al., Semi Oncol 28:15. 2001). In addition, even low doses of doxorubicin in combination with paclitaxel cause cardiotoxicity as demonstrated by reductions in left ventricular ejection fraction (Sparano J A et al., J Cin Oncol 17: 3828, 1999).